Next-generation sequencing informs diagnosis and identifies unexpected therapeutic targets in lung squamous cell carcinomas

Our plain-English summary of Next-generation sequencing informs diagnosis and identifies unexpected therapeutic targets in lung squamous cell carcinomas, by J.M. Sands, T. Nguyen, P. Shivdasani, et al (Lung Cancer, 2020).

The study

• Authors: J.M. Sands, T. Nguyen, P. Shivdasani, A.G. Sacher, M.L. Cheng, R.S. Alden, P.A. Jänne, F.C. Kuo, G.R. Oxnard, L.M. Sholl
• Journal: Lung Cancer
• Published: 2020;140:35-41
• Cited by: 43 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Potentially targetable genomic alterations have been identified in lung squamous cell carcinoma (LUSC), but none have yet translated into effective therapy. We examined potential benefits of next generation sequencing (NGS) in a cohort of consecutive LUSC patients with emphasis on distinctions between smokers and light/never smokers and implications for clinical trial enrollment.

Methods: We retrospectively evaluated results from an internally developed NGS assay (OncoPanel) targeting ∼300 genes with a mean overall target coverage of >200x for consecutive LUSC seen at our institution over 30 months.

Results: Tissue was obtained from 172 patients for targeted NGS. 42 (24 %) samples were insufficient for testing. Median age of tested patients was 66, including 87 % moderate/heavy versus 13 % light/never smokers; 66 % were stage IIIB or IV. Of 130 patients with evaluable NGS results, 49 (38 %) had at least 1 alteration qualifying for enrollment to a LungMAP treatment arm (PIK3CA, MET, FGFR family, cell cycle, or homologous recombination pathways) or for an approved therapy or other clinical trial (e.g. EGFR sensitizing mutations, MET exon 14 splice mutations, TSC1/2 mutation, or microsatellite instability). Therapeutic targets were enriched in light/never smokers (47 % vs 35 % moderate/heavy smokers). Unexpectedly, genomic features suggested an alternative diagnosis (metastatic cutaneous squamous carcinoma; mesothelioma) in 7 patients, including 35 % of never/light smokers.

Conclusion: NGS in a real-world LUSC cohort yields potentially targetable genomic alterations informing clinical trial enrollment and approved therapies and critical diagnostic insights. Our findings strongly support current guidelines recommending mutational profiling of LUSC arising in light/never smoking patients; the utility of sequencing in smokers with LUSC appears to be limited to identification of research targets.

Copyright © 2019 Elsevier B.V. All rights reserved.

In plain English

This study looked back at genetic testing of tumors from 172 patients with lung squamous cell carcinoma, a type of lung cancer, enrolled at the Dana-Farber Cancer Institute in Boston between July 2013 and February 2016. Tumor samples were tested with a panel covering about 300 genes. 130 samples gave usable results, and 42 (24%) were insufficient for testing. The authors compared never or light smokers with moderate or heavy smokers. Of the 130 tested patients, 49 (38%) had at least one alteration that could qualify them for a clinical trial or an approved treatment. This applied to 8 of 17 (47%) never or light smokers and to 35% of moderate or heavy smokers. In six cases the mutation pattern matched ultraviolet light damage, raising the possibility of spread from skin cancer. In one never smoker, first diagnosed from a pleural biopsy at age 47, the genetic profile resembled malignant mesothelioma. The article does not discuss asbestos. The authors concluded that their findings support mutation testing in light or never smokers.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective review of tumor genetic sequencing (next-generation sequencing) results in a series of consecutive patients
• Who was studied: 172 patients with lung squamous cell carcinoma at the Dana-Farber Cancer Institute, Boston, enrolled July 1, 2013 to February 1, 2016; 130 had usable sequencing results
• Exposure: No asbestos exposure was studied. The comparison was by smoking history: never or light smokers (less than 10 pack-years) versus moderate or heavy smokers
• Main results:
  • 42 of the 172 samples (24%) were insufficient for sequencing
  • Of 130 patients with usable results, 49 (38%) had at least one alteration qualifying for a LungMAP trial arm, an approved therapy, or another clinical trial
  • Potential treatment targets were found in 47% of light/never smokers (8 of 17) versus 35% of moderate/heavy smokers
  • Six tumors showed an ultraviolet-light mutation pattern: 5 in never/light smokers and one in a heavy smoker. All of those never/light smokers had a documented history of previously removed skin squamous cell carcinoma
  • One patient's tumor had a genetic profile resembling malignant mesothelioma (BAP1 mutation with deletion, loss of CDKN2A, one-copy loss of NF2). This patient was a never smoker originally diagnosed with squamous cell carcinoma on a pleural biopsy at age 47
  • After removing tumors with the ultraviolet pattern, mean tumor mutational burden was 7.2 (median 7.9) in light/never smokers versus 12.0 (median 10.6) in moderate/heavy smokers (p = 0.05). Before removal it was 17.6 versus 12.2 (p = 0.42)
• The authors' conclusion: The authors concluded that their findings support guidelines recommending mutation testing of lung squamous cell carcinoma in light/never smokers. They concluded that in smokers, the usefulness of sequencing appears limited to identifying research targets.
• Limitations the authors state:
  • Two-thirds of diagnoses were based on small biopsies, which sample only part of the tumor and may miss an adenocarcinoma component
  • Tumor mutational burden may be measured less precisely in tumors with very low tumor content
  • Inherited (germline) sequencing was unavailable for most patients with repair-pathway mutations

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Next-Generation Sequencing (NGS), Squamous Cell Carcinoma, Clinical Trial, EGFR, Microsatellite Instability (MSI-H), Carcinoma, Mesothelioma.

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